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Effect of protein mutations on ligand efficacy.

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posted on 24.11.2021, 18:34 by Willem Jespers, Laura H. Heitman, Adriaan P. IJzerman, Eddy Sotelo, Gerard J. P. van Westen, Johan Åqvist, Hugo Gutiérrez-de-Terán

(A) Binding mode of the agonist CGS21680 to the WT A2AAR (left), T88A (center) and S277A (right) mutant forms of this receptor, simulated by FEP simulations (H-bonds in yellow dashed lines with residues involved in sticks). (B) Thermodynamic cycles representing the effect of a point mutation (mut) on the distribution of inactive (R) and active (R*) states of the receptor (left side, dense dashed), and on the affinity of a ligand (L) for the active state (right side, light dashed). The combination of the two thermodynamic cycles would yield the net effect of the mutation ligand efficacy. (C) Calculated effects of point mutations on the A2AAR constitutive activity (ΔΔGR* →R, dense dashed columns), and on the ligand relative affinity for R* (ΔΔGL-R*, light dashed columns), following the corresponding thermodynamic cycles depicted in (A). The overall effect of the mutation on the shift in ligand efficacy, (, solid blue) is calculated by combination of these two values, showing correlation with the experimental values (, solid orange, see text).